Research Article Synthesis, Crystal Structure, and ...downloads.hindawi.com/archive/2014/936174.pdfAttribution License, which permits unrestricted use, distributio n, and reproduction

Research ArticleSynthesis, Crystal Structure, and Hirshfeld Surface Analysis ofCiprofloxacin-Salicylic Acid Molecular Salt

Ravikumar Nagalapalli and Shankar Yaga Bheem

Department of Chemistry, BABA Institute of Technology & Sciences, Visakhapatnam 530048, India

Correspondence should be addressed to Ravikumar Nagalapalli; [email protected]

Received 27 December 2013; Accepted 21 February 2014; Published 7 April 2014

Academic Editor: Mehmet Akkurt

Copyright © 2014 R. Nagalapalli and S. Yaga Bheem. This is an open access article distributed under the Creative CommonsAttribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work isproperly cited.

In the present study, ciprofloxacin-salicylic acid molecular salt has been synthesized and preliminarily characterized by FT-IRspectroscopy. The single crystal X-ray diffraction (SCXRD) reveals the proton transfer from carboxylic acid group of salicylic acidto piperazine moiety in ciprofloxacin confirming the formation of new molecular salt. The molecular packing of the molecularsalt is mainly supported by N+–H⋅ ⋅ ⋅O−, O–H⋅ ⋅ ⋅O, C–H⋅ ⋅ ⋅ F, C–H⋅ ⋅ ⋅ 𝜋, and 𝜋-𝜋 interactions. The 3D Hirshfeld surfaces and theassociated 2D fingerprint plots were investigated for intermolecular hydrogen bonding interactions.

1. Introduction

In the pharmaceutical industry salt formation is a widely usedmethod tomodulate the physicochemical properties of activepharmaceutical ingredients (APIs) [1]. Salts have been shownto modulate the solubility and bioavailability of APIs [2–4].An active pharmaceutical salt is a combination of an APIwith the GRAS (generally regarded as safe by US FDA) listedcoformer [5]. A crystal engineering approach in the selectionof acid or base for a given drug molecule to make salts orcocrystals is reported in the literature [6, 7]. Hydrochloridesalts are the most preferred method to improve the solubilityand stability of APIs [1], but hygroscopicity is a drawbackfor the hydrochloride salts [8]. Ciprofloxacin (CPF) is asynthetic antibacterial fluoroquinolone related to nalidixicacid having a fluorine atom and piperazine ring at thepositions 6 and 7 of quinolone-3-carboxylic acid. It is oneof the most active fluoroquinolones with a wide spectrum ofbiological activity, which is active against both Gram-positive[9] and Gram-negative bacteria [10]. In recent years, CPFhas drawn great interest from crystal engineers, due to itstendency to form robust supramolecular architectures withcompounds having carboxylic acid functional groups, andalso various salts of ciprofloxacin are reported in [11–16].Our endeavours in the present study are synthesis of CPF

molecular salt with GRAS listed salicylic acid, determinationof crystal structure by SCXRD, and investigation of variousintra- and intermolecular hydrogen bonding by Hirshfeldsurface analysis. The molecular structures of CPF and SA areshown in Figure 1.

2. Materials and Methods

2.1. Materials. Ciprofloxacin (purity 98%) and salicylicacid (purity 99%) were purchased from Alfa Aesar, India.Methanol with HPLC grade purity was obtained fromRankem,, India, and used without further purification. Dis-tilled water was used for crystallization.

2.2. Synthesis of CPF-SAMolecular Salt. A 1 : 1 stoichiometricratio of CPF (33mg, 0.1mmol) and SA (13.8mg, 0.1mmol)was dissolved in methanol (5mL) and water (5mL) mixtureat 60∘C for 10 minutes, and the resulting solution is filtered,cooled, and left for slow evaporation at room temperature.Colorless prism shape crystals of CPF-SA salt, suitable forsingle crystal X-ray analysis, were obtained after 2 days.

2.3. Infrared Spectroscopy (FT-IR). ABruker Alpha-T Fouriertransform infrared spectrophotometer in the spectral range4000 to 600 cm−1 with resolution of 2 cm−1 was used to

Hindawi Publishing CorporationJournal of CrystallographyVolume 2014, Article ID 936174, 5 pageshttp://dx.doi.org/10.1155/2014/936174

2 Journal of Crystallography

O

N

F

N

NH

O

HO

(a)

HO O

OH

(b)

Figure 1: Chemical diagrams of ciprofloxacin (a) and salicylic acid(b).

record the infrared spectra of the samples with the KBr pelletmaking technique.

2.4. Single Crystal X-Ray Diffraction (SCXRD). Single crystalX-ray diffraction data was collected at 298 (1) K on RigakuMercury diffractometer using a single wavelength EnhanceX-ray source with Mo 𝐾

𝛼radiation (𝜆 = 0.71070 A). The

Crystal Clear [17] program was used for data collectionand cell refinement. The Crystal Structure [17] program wasused for data reduction. The structure was solved by SIR92[18] program and CRYSTALS [19] program was used forstructure refinement.The ORTEP [20] program was used formolecular graphics. All the H positions bound to C atomswere calculated after each cycle of refinement using a ridingmodel C−H=0.95 A and𝑈iso(H) = 1.2𝑈eq(C). All theH atomsbound to N and O atoms were located in different Fouriermaps and freely refined. The crystallographic details weresummarized in Table 1.

2.5.Theoretical Calculation. MolecularHirshfeld surfaces aregenerated by CrystalExplorer [21] computer program.

3. Results and Discussion

The CPF-SA molecular salt crystallizes in triclinic spacegroup 𝑃-1. The crystal structure of CPF-SA molecular salthas one ciprofloxacin cation, one salicylate, and one-halfO2(Figure 2). The carboxylic acid group of CPF is in

unionized state because the C–O and C=O bond distancesdiffer by greater than 0.1 A and are involved in intramolecularhydrogen bondingwith the quinolone carbonyl oxygen atom.The carboxylate moiety C–O bond distances are about nearequal (difference < 0.03 A). The carboxylic acid group inCPF is planar to the quinolone ring, as evidenced by thetorsion angle (C5–C6–C10–O1 = 175.8∘). A carboxylic acidgroup in salicylic acid transfers proton to the nitrogen atomof the piperazine moiety in CPF, thereby forming a salicylateanion and CPF cation. Proton transfer is evidenced by thedifference between the C–O bond distances C(18)–O(5) =1.264(2) A and C(18)–O(4) = 1.249(2) A of the carboxylategroup in salicylate moiety with the ΔDC−O value of 0.015 A.The relatively small ΔDC−O value confirmed the formationof carboxylate group [22]. The piperazinium moiety in CPFadopts chair conformation.TheCPF aromaticmolecular coreis 𝜋-stacked infinitely along the crystallographic 𝑏-axis at

Table 1: The crystal and experimental data.

Empirical formula C24H24FN3O7

Formula weight 485.46Crystal system TriclinicSpace group P-1𝑇 (K) 298(1)𝜆 (A) 0.71070𝑎 (A) 6.9532(10)𝑏 (A) 9.8979(11)𝑐 (A) 17.212(2)𝛼 (∘) 79.397(19)𝛽 (∘) 85.53(2)𝛾 (∘) 83.09(2)𝑉 (A3) 1154.0(3)𝑍 2𝐷cal (g cm

−3) 1.397𝜇 (mm−1) 0.109𝐹 (0 0 0) 508Crystal size (mm) 0.20 × 0.20 × 0.20

Crystal shape and color Prism, colorless𝜃range (

∘) 2.4 to 27.4ℎ −8→ 7𝑘 −12→ 12𝑙 −21→ 21Reflections collected 4623Reflections unique 4575/𝑅int = 0.039

Absorption correction Multi-scanGoodness-of-fit on 𝐹2 1.18𝑅

1and 𝑤𝑅

2indices (all data) 0.055, 0.057

Δ𝜌max, Δ𝜌min (e⋅A−3) 0.26 and −0.29

CCDC 968489

3.58 A distance. The CPF cations reside in the 𝑎𝑏-plane andthe salicylate anions are perpendicular to it (along the 𝑐-axis). The molecular packing of the crystal is also stabilizedby C–H⋅ ⋅ ⋅ F interactions. The overall crystal packing of themolecular salt is shown in Figure 3. Selected bond lengths,bond angles, torsion angles, and possible hydrogen bondinginteractions are given in Table 2.

FT-IR spectroscopy is a widely used technique in thecharacterization of the formation of new solid phases. Theinfrared peaks of the –COOH group of CPF resonate at 1696and 1262 cm−1 due to C=O and C–O stretch, respectively.Thebroad peak at 2424 cm−1 is attributed to the protonated piper-azine nitrogen atom (NH

2

+) [23]. Moreover, the appearanceof two characteristic carboxylate IR absorption vibrations at1574 and 1337 cm−1 due to asymmetric and symmetric O–C–O stretch, respectively, confirmed the proton transfer fromthe –COOH group in SA.

The 3D Hirshfeld surfaces and 2D fingerprint mapsare unique for each molecule in the asymmetric unit of agiven crystal. Hirshfeld surfaces provide a three-dimensionalpicture of intermolecular interactions in a crystal [24]. ForCPF-SA molecular salt, N–H⋅ ⋅ ⋅O and O–H⋅ ⋅ ⋅O hydrogen

Journal of Crystallography 3

O3O2

O1

C10

C6

C5

C7 N3

C4

C8

C9

C3

C2

C1

F1

C16

C17

N2

N1

C15C14

O5

O4

C18

O6

C23

C22

C24

C21

C19

C20

C11

C13

C12 O7

O8

Figure 2: ORTEP diagram of CPF-SA molecular salt, showing 50% probability ellipsoids.

Figure 3: Crystal packing diagram of CPF-SA molecular salt.

4 Journal of Crystallography

Table 2: Geometrical parameters.

(a) Selected bond lengths (A), bond angles (∘), and torsion angles (∘)

F1–C2 1.3619(13) N1–C16 1.488(2)O1–C10 1.215(2) N1–C15 1.483(2)O2–C10 1.3318(19) N2–C1 1.3857(16)O3–C5 1.2635(16) N2–C14 1.4645(18)O4–C18 1.249(2) N2–C17 1.4786(19)O5–C18 1.264(2) N3–C11 1.4589(17)O6–C24 1.346(2) N3–C7 1.3484(17)O7–O8 1.045(4) N3–C8 1.4085(16)C15–N1–C16 110.77(11) N3–C8–C9 120.21(11)C14–N2–C17 111.31(11) O2–C10–C6 115.56(13)C1–N2–C14 118.30(11) O1–C10–C6 123.16(13)C1–N2–C17 120.91(11) O1–C10–O2 121.28(13)C7–N3–C11 120.32(11) N3–C11–C13 118.98(12)C7–N3–C8 119.30(11) N3–C11–C12 118.65(12)C8–N3–C11 120.29(10) N2–C14–C15 111.16(12)N2–C1–C9 122.20(12) N1–C15–C14 111.17(12)N2–C1–C2 121.91(12) N1–C16–C17 109.93(13)F1–C2–C1 119.16(11) N2–C17–C16 109.68(12)F1–C2–C3 117.41(12) O4–C18–C19 118.77(15)O3–C5–C4 121.59(12) O5–C18–C19 119.49(13)O3–C5–C6 123.06(12) O4–C18–O5 121.72(16)N3–C7–C6 124.37(13) O6–C24–C23 118.18(18)N3–C8–C4 118.97(11) O6–C24–C19 121.39(17)C1–N2–C14–C15 157.17(12) C7–N3–C8–C9 178.24(11)C10–C6–C7–N3 179.51(12) N3–C8–C9–C1 176.34(11)

(b) Hydrogen bonding interactions

Interaction D–H/A H⋅ ⋅ ⋅A/A D⋅ ⋅ ⋅A/A <D–H⋅ ⋅ ⋅A/∘

O6–H60⋅ ⋅ ⋅O4 0.96(2) 1.64(2) 2.357(3) 152.5(19)N1–H100⋅ ⋅ ⋅O4i 0.976(14) 2.473(15) 3.105(2) 122.2(11)N1–H100⋅ ⋅ ⋅O5i 0.976(14) 1.755(14) 2.722(18) 170.8(13)N1–H101⋅ ⋅ ⋅O7ii 0.943(15) 1.873(15) 2.803(3) 168.1(15)N1–H101⋅ ⋅ ⋅O8ii 0.943(15) 1.849(15) 2.740(3) 156.5(15)O2–H201⋅ ⋅ ⋅O3 0.93 1.67(2) 2.562(16) 161.6(19)C7–H7⋅ ⋅ ⋅O1 0.95 2.480 2.811(18) 101.0C12–H121⋅ ⋅ ⋅O1iii 0.95 2.530 3.479(2) 174.0C15–H121⋅ ⋅ ⋅O2iv 0.95 2.590 3.395(18) 143.0C16–H162⋅ ⋅ ⋅O6v 0.95 2.490 3.371(2) 154.0C17–H171⋅ ⋅ ⋅ F1 0.95 2.170 2.862(2) 129.0Symmetry codes: (i) −𝑥 + 2, −𝑦 + 1, −𝑧 + 1 (ii) −𝑥 + 1, −𝑦 + 1, −𝑧 + 1(iii) −𝑥 + 1, −𝑦 + 2, −𝑧 + 2 (iv) −𝑥 + 2, −𝑦 + 1, −𝑧 + 2 (v) 𝑥, 𝑦 − 1, 𝑧.

bonding intermolecular interactions appear as two smallspikes (upper left spike is sharp and lower right spike is broad)in the 2D fingerprint map, which have the most significantcontribution to the total Hirshfeld surfaces of 1, comprised of36.6%. The H–H interactions, which appeared in the middleof scattered points in the 2D fingerprint map, are comprisedof 34.0% of the total Hirshfeld surfaces. The C–H⋅ ⋅ ⋅ F inter-actions also have a relatively significant contribution to the

(a)

2.4

2.2

2.0

1.8

1.6

1.4

1.2

1.0

0.8

0.6

2.42.22.01.81.61.41.21.00.80.6

de

di

(b)

Figure 4: Hirshfeld surface (a) and 2D fingerprint map (b).

total Hirshfeld surfaces of CPF-SAmolecular salt, comprisedof 6.0%.Apart from those above interactions, the other𝜋 ⋅ ⋅ ⋅ 𝜋(C–C), lone-pair⋅ ⋅ ⋅ 𝜋 (O–C), and lone-pair⋅ ⋅ ⋅ lone-pair (O–O) interactions are also observed. The 3D Hirshfeld surfacesand 2D fingerprint maps of CPF-SAmolecular salt are shownin Figure 4.

4. Conclusions

To summarize, we have reported synthesis, X-ray crystalstructure analysis, and the Hirshfeld surfaces analyses ofciprofloxacin-salicylic acid molecular salt. The formation ofthe molecular salt was further characterized and confirmedby FT-IR analysis. The crystal structure of the salt is mainlystabilized by N+−H⋅ ⋅ ⋅O−, O−H⋅ ⋅ ⋅O, C−H⋅ ⋅ ⋅ F, and 𝜋-𝜋interactions. The 3D Hirshfeld surface analysis and 2Dfingerprint maps analysis revealed that N–H⋅ ⋅ ⋅O and O–H⋅ ⋅ ⋅O hydrogen bonding intermolecular interactions aremore prominent in the salt.

Journal of Crystallography 5

Conflict of Interests

The authors declare that there is no conflict of interestsregarding the publication of this paper.

Acknowledgments

Theauthors sincerely thank theManagement, BITSVizag, fortheir financial support and encouragement.

References

[1] M. Pudipeddi, A. T. M. Serajuddin, D. J. W. Grant, and P. H.Stahl, “Solubility and dissolution of weak acids, bases, and salts,”in Handbook of Pharmaceutical Salts, Properties, Selection andUse, P. H. Stahl and C. G. Wermuth, Eds., pp. 19–40, Wiley-VCH, Weinheim, Germany, 1st edition, 2002.

[2] S. L. Childs, L. J. Chyall, J. T. Dunlap, V. N. Smolenskaya, B.C. Stahly, and G. P. Stahly, “Crystal engineering approach toforming cocrystals of amine hydrochlorides with organic acids.Molecular complexes of fluoxetine hydrochloride with benzoic,succinic, and fumaric acids,” Journal of the American ChemicalSociety, vol. 126, no. 41, pp. 13335–13342, 2004.

[3] S. N. Black, E. A. Collier, R. J. Davey, and R. J. Roberts,“Structure, solubility, screening, and synthesis of molecularsalts,” Journal of Pharmaceutical Sciences, vol. 96, no. 5, pp. 1053–1068, 2007.

[4] R. Banerjee, P. M. Bhatt, N. V. Ravindra, and G. R. Desiraju,“Saccharin salts of active pharmaceutical ingredients, theircrystal structures, and increased water solubilities,” CrystalGrowth and Design, vol. 5, no. 6, pp. 2299–2309, 2005.

[5] G. Patrick Stahly, “A survey of cocrystals reported prior to 2000,”Crystal Growth and Design, vol. 9, no. 10, pp. 4212–4229, 2009.

[6] O. Almarsson and M. J. Zaworotko, “Crystal engineering ofthe composition of pharmaceutical phases. Do pharmaceuticalco-crystals represent a new path to improved medicines?”Chemical Communications, vol. 10, no. 17, pp. 1889–1896, 2004.

[7] N. Blagden,M. deMatas, P. T. Gavan, and P. York, “Crystal engi-neering of active pharmaceutical ingredients to improve solu-bility and dissolution rates,” Advanced Drug Delivery Reviews,vol. 59, no. 7, pp. 617–630, 2007.

[8] S. M. Berge, L. D. Bighley, and D. C. Monkhouse, “Pharmaceu-tical salts,” Journal of Pharmaceutical Sciences, vol. 66, no. 1, pp.1–19, 1977.

[9] F. H. Kayser and J. Novak, “In vitro activity of ciprofloxacinagainst gram-positive bacteria. An overview,” American Journalof Medicine, vol. 82, no. 4 A, pp. 33–39, 1987.

[10] J. E. Rudin, C. W. Norden, and E. M. Shinners, “In vitro activ-ity of ciprofloxacin against aerobic gram-negative bacteria,”Antimicrobial Agents and Chemotherapy, vol. 26, no. 4, pp. 597–598, 1984.

[11] J. S. Reddy, S. V. Ganesh, R. Nagalapalli et al., “Fluoroquinolonesalts with carboxylic acids,” Journal of Pharmaceutical Sciences,vol. 100, no. 8, pp. 3160–3176, 2011.

[12] I. Turel and A. Golobic, “Crystal structure of ciprofloxacinhydrochloride 1.34-hydrate,” Analytical Sciences, vol. 19, no. 2,pp. 329–330, 2003.

[13] B. Lou,D. Bostrom, and S. P. Velaga, “Monohydrous dihydrogenphosphate salts of norfloxacin and ciprofloxacin,” Acta Crystal-lographica Section C: Crystal Structure Communications, vol. 63,no. 12, pp. o731–o733, 2007.

[14] M. D. Prasanna and T. N. Guru Row, “Hydrogen bondednetworks in hydrophilic channels: crystal structure of hydratedciprofloxacin lactate and comparison with structurally similarcompounds,” Journal of Molecular Structure, vol. 559, no. 1–3,pp. 255–261, 2001.

[15] X. Li, Y. Hu, Y. Gao, G. G. Z. Zhang, and R. F. Henry, “Amethanol hemisolvate of ciprofloxacin,” Acta CrystallographicaSection E: Structure Reports Online, vol. 62, no. 12, pp. o5803–o5805, 2006.

[16] I. Turel, P. Bukovec, and M. Quiros, “Crystal structure ofciprofloxacin hexahydrate and its characterization,” Interna-tional Journal of Pharmaceutics, vol. 152, no. 1, pp. 59–65, 1997.

[17] Rigaku/MSC and Rigaku Corporation, CrystalClear (VersionSM-1. 4. 0 B2) and CrystalStructure (Version 3. 8). Single CrystalStructure Analysis Software, Rigaku/MSC, Tokyo, Japan, 2006.

[18] A. Altomare, G. Cascarano, C. Giacovazzo et al., “SIR92—aprogram for automatic solution of crystal structures by directmethods,” Journal of Applied Crystallography, vol. 27, no. 3, p.435, 1994.

[19] P. W. Betteridge, J. R. Carruthers, R. I. Cooper, K. Prout, andD. J. Watkin, “CRYSTALS version 12: software for guided crystalstructure analysis ,” Journal of Applied Crystallography, vol. 36,p. 1487, 2003.

[20] P. McArdle, “ORTEX—an interactive version of ORTEP for useon a PC,” Journal of Applied Crystallography, vol. 26, p. 752, 1993.

[21] S. K. Wolff, D. J. Grimwood, J. J. McKinnon, D. Jayatilaka, andM. A. Spackman, CrystalExplorer, Version 1. 5, University ofWestern Australia, Perth, Australia, 2007.

[22] R. Chada, A. Saini, S. Khullar, D. S. Jain, S. K. Mandal,and T. N. Guru Row, “Crystal structures and physicochemicalproperties of four new lamotrigine multicomponent forms,”Crystal Growth and Design, vol. 13, pp. 858–870, 2013.

[23] S. Basavoju, D. Bostrom, and S. P. Velaga, “Pharmaceuticalcocrystal and salts of norfloxacin,” Crystal Growth and Design,vol. 6, no. 12, pp. 2699–2708, 2006.

[24] M. A. Spackman and J. J. McKinnon, “Fingerprinting inter-molecular interactions in molecular crystals ,” CrystEngComm,vol. 4, pp. 378–392, 2002.

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Research Article Synthesis, Crystal Structure, and ...downloads.hindawi.com/archive/2014/936174.pdfAttribution License, which permits unrestricted use, distributio n, and reproduction